Nicotine, Neurotrophins and Depression

尼古丁、神经营养素和抑郁症

• 批准号: 7163147
• 负责人: YOUSEF TIZABI
• 金额: $ 15.77万
• 依托单位: HOWARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7163147
• 关键词: amines; antidepressants; behavior test; depression; dopamine receptor; gas chromatography mass spectrometry; high performance liquid chromatography; laboratory rat; microdialysis; neurotransmitter receptor; nicotine; nicotinic receptors; norepinephrine; pharmacokinetics; psychopharmacology; receptor binding; receptor sensitivity; serotonin receptor; statistics /biometry; stereotaxic techniques

Because of high incidence of cigarette smoking among depressed individuals, it has been postulated that smoking may reflect an attempt at self-medication with nicotine by these individuals. However, other studies suggest that smoking may precede depression. Recent findings by us and others depict a complex involvement of nicotine and nicotinic system in mood regulation. Thus, nicotine acutely or chronically may act as an antidepressant in Fliners Sensitive Line (FSL) rats, a strain with inherent depressive-like behavior. However, in WKY rats, another putative animal model of depression, depending on the administered regimen, nicotine may act as an antidepressant or a "depressogenic" agent by exacerbating the depressive characteristics of these rats. Hence, the questions of when and how nicotine may act as an antidepressant or a depressogenic or what central mechanisms may mediate its effects remain unanswered. Recent findings strongly suggest that the brain-derived neurotrophic factor (BDNF) may be a common denominator in the mechanism of action of all antidepressants. Hence, the major aim of this proposal is to elucidate the interactions between nicotine, BDNF and its high affinity receptor Trk-B in relation to depression. Specifically, the following hypotheses will be evaluated: 1. Antidepressant effects of nicotine will be associated with an increase in BDNF and Trk-B densities in hippocampal and other areas implicated in mood regulation, and the "depressogenic" effects of nicotine will be associated with an opposite effect on these parameters. 2. The antidepressant effects of nicotine will be associated with an anti-apoptotic activity and depressogenic effects of nicotine will be associated with a pro-apoptotic activity. 3. Clinically effective antidepressants that are also effective in this model will increase BDNF, Trk-B and antiapoptotic activities. 4. Clinically effective antidepressants that are not effective in this model will not affect BDNF or apoptotic activities. 5. Serum BDNF levels will be decreased in depressive states and effective antidepressants will elevate serum BDNF levels. Behavioral analyses will include Porsolt forced swim test and general locomotor activity. BDNF and TrkB containing neurons will be quantified by immunocytochemical and state of the art stereological techniques. TUNEL staining and stereological quantification will be applied to determine the extent of apoptosis. Enzyme-linked immunosorbent assay (ELISA) will be used to quantify the serum levels of BDNF. The results of these studies can: 1. provide answers to the seemingly contradictory effects of nicotine on mood, 2. indicate a common determinant for antidepressant effectiveness, and 3. suggest a possible peripheral marker for the depressive state and/or efficacy of antidepressant treatments. The findings may also facilitate the development and evaluation of novel antidepressants and/or compounds useful in smoking cessation.

由于抑郁症患者吸烟的比例很高，因此有人推测： 吸烟可能反映出这些人试图用尼古丁进行自我治疗。然而，其他研究 表明吸烟可能先于抑郁症。我们和其他人的最新发现描绘了一个复杂的 尼古丁和烟碱系统参与情绪调节。因此，尼古丁急性或慢性可能 作为 Fliners 敏感系 (FSL) 大鼠的抗抑郁药，FSL 是一种具有固有抑郁样行为的品系。 然而，在 WKY 大鼠（另一种假定的抑郁症动物模型）中，取决于所施用的药物 治疗方案中，尼古丁可能通过加剧抑郁症而充当抗抑郁药或“致抑郁”剂。 这些老鼠的特征。因此，尼古丁何时以及如何充当抗抑郁药的问题 或抑郁症或什么中央机制可能介导其影响仍然没有答案。最近的 研究结果强烈表明脑源性神经营养因子（BDNF）可能是一个共同点 在所有抗抑郁药的作用机制中。因此，本提案的主要目的是阐明 尼古丁、BDNF 及其高亲和力受体 Trk-B 之间的相互作用与抑郁症相关。具体来说， 将评估以下假设： 1. 尼古丁的抗抑郁作用将与 海马和其他与情绪调节有关的区域 BDNF 和 Trk-B 密度增加，以及 尼古丁的“抑郁”作用将与对这些参数的相反作用相关。 2. 的 尼古丁的抗抑郁作用与抗凋亡活性和抑郁作用有关 尼古丁与促凋亡活性有关。 3. 临床上有效的抗抑郁药 在该模型中有效会增加 BDNF、Trk-B 和抗凋亡活性。 4、临床有效 在此模型中无效的抗抑郁药不会影响 BDNF 或细胞凋亡活性。 5. 血清 抑郁状态下 BDNF 水平会降低，有效的抗抑郁药物会升高血清 BDNF 水平。行为分析将包括 Porsolt 强迫游泳测试和一般运动活动。脑源性神经营养因子和 含有 TrkB 的神经元将通过免疫细胞化学和最先进的体视学进行定量 技术。将应用 TUNEL 染色和体视定量来确定 细胞凋亡。酶联免疫吸附测定 (ELISA) 将用于量化 BDNF 的血清水平。 这些研究的结果可以： 1. 为尼古丁看似矛盾的影响提供答案。 情绪，2. 指出抗抑郁药有效性的共同决定因素，以及 3. 提出可能的 抑郁状态和/或抗抑郁治疗功效的外周标志物。研究结果可能 还促进新型抗抑郁药和/或用于吸烟的化合物的开发和评估 停止。